Melatonin, ganglia and sleep disturbance in heart disease

There is a direct cause behind sleep disturbances in people suffering from heart conditions. These findings may have even greater population significance following other recent clinical papers reporting heart damage after COVID-19 vaccination affecting as many as one in thirty five people.

The cause of sleep disturbance in heart disease has now been identified.

  • Trigger for sleep disturbances in heart patients found in loss of nerves in the pineal gland
  • These nerves originate in a neuron cluster (ganglion) in the neck region where adjacent nerve cells control the heart and pineal gland function
  • Previously unrecognized role of ganglia as a link between widely separated organs
  • Melatonin production normalized with drugs in an animal experiment

Around one third of people with heart disease suffer from sleep problems. In a paper published in the journal Science, a team at the Technical University of Munich (TUM) shows that heart diseases affect the production of the sleep hormone melatonin in the pineal gland. The link between the two organs is a ganglion in the neck region. The study demonstrates a previously unknown role of ganglia and points to possible treatments.

Dr StefanThe fact that melatonin levels can decrease in patients with diseases of the heart muscle, for example after a heart attack, has been known for some time. This has generally been seen as a further example of how a heart condition acts systemically on the entire body. A team working with Stefan Engelhardt, (pictured) Professor of Pharmacology and Toxicology at TUM, and first author Dr. Karin Ziegler, has now shown that there is a direct cause behind sleep disturbances in people suffering from heart conditions.

Ganglia as “electrical switchboxes”

“In our work, we show that the problems with the heart muscle affect an organ that would seem at first glance to have no direct link to it,” says Stefan Engelhardt. Melatonin is produced in the pineal gland, located inside the brain. Like the heart, it is controlled through the autonomic nervous system, which regulates involuntary processes in the body. The related nerves originate in the ganglia, among other places. Particularly important for the heart and pineal gland is the superior cervical ganglion. 

“To get a clear sense of our results, imagine the ganglion as an electrical switchbox. In a patient suffering from sleep disturbances following a heart disease, you can think of a problem with one wire causing a fire to break out in the switchbox and then spreading to another wire,” says Stefan Engelhart.

Nerve connection to pineal gland destroyed in mice and humans

The team discovered that macrophages – cells that eat dead cells – accumulate in the cervical ganglion of mice with heart disease. The exact mechanisms behind this are still unknown. The macrophages cause inflammation and scarring in the ganglion and the destruction of nerve cells. In mice, as in humans, long fibers extending from these nerve cells, called axons, lead to the pineal gland. At advanced stages of disease, there was a substantial decrease in the number of axons connecting the gland to the nervous system. There was less melatonin in the bodies of the animals and their day/night rhythm was disrupted.

Comparable organic effects were seen in humans. The team investigated the pineal glands in nine heart patients. Compared to the control group, significantly fewer axons were found. As with the mice, the superior cervical ganglion in the humans with heart disease showed scarring and was noticeably enlarged.

Starting point for new drugs

The researchers assume that the negative effects of the dead axons become permanent at an advanced stage. “In an early stage we were able to return melatonin production in mice to the original level by using drugs to destroy the macrophages in the superior cervical ganglion,” says Karin Ziegler. “First, this demonstrates the role of the ganglion in this phenomenon. And second, it inspires hope that we can develop drugs to prevent irreparable sleep disturbances in heart disease.” That is one of the tasks the team wishes to address in the coming years.

Investigating ganglia for other possible connections

Along with new hope for a large number of heart patients that a treatment will be found for sleep disturbances, Stefan Engelhardt sees the study as a reason to look at the ganglia from a new vantage point. “New methods such as spatial single cell sequencing make it possible to investigate individual nerve cells much more closely. Our study could prompt researchers to start systematically searching for connections between other diseases in organs linked via ganglia acting as switchboxes and to look at ganglia as starting points in the search for new drugs.” 

Engelhardt believes that ganglia could also become important from a diagnostic standpoint. Because all of the cervical ganglia in the heart patients they examined were significantly enlarged, the researchers believe that this may be an indicator of heart failure. The size of the ganglion can be checked easily with a conventional ultrasound device. If the results are confirmed in further studies, it may be advisable to order more extensive checks of the heart when the ganglion is found to be enlarged.


K.A. Ziegler, A. Ahles, A. Dueck, D. Esfandyari, P. Pichler, K. Weber, S. Kotschi, A. Bartelt, I. Sinicina, M. Graw, H. Leonhardt, L. Weckbach, S.  Massberg, M. Schifferer, M. Simons, L. Hoeher, J. Luo, A. Ertürk, G.G. Schiattarella, Y. Sassi, T. Misgeld, S. Engelhardt. “Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease”. Science (2023).

The part of the nervous system supplying muscles such as the heart and bowels, known as involuntary muscles. Full medical glossary
Relating to the heart Full medical glossary
The basic unit of all living organisms. Full medical glossary
Relating either to the cervix (the neck of the womb) or to the cervical vertebrae in the neck (cervical spine). Full medical glossary
The basic unit of genetic material carried on chromosomes. Full medical glossary
An organ with the ability to make and secrete certain fluids. Full medical glossary
The death of a section of heart muscle caused by an interruption in its blood supply. Also called a myocardial infarction. Full medical glossary
Failure of the heart to pump adequately. Full medical glossary
A substance produced by a gland in one part of the body and carried by the blood to the organs or tissues where it has an effect. Full medical glossary
The body’s response to injury. Full medical glossary
A large cell that is present in many different organs and tissues. One of its functions is the removal of bacteria and other foreign bodies from the body. Full medical glossary
Tissue made up of cells that can contract to bring about movement. Full medical glossary
Bundle of fibres that carries information in the form of electrical impulses. Full medical glossary
Bundles of fibres that carry information in the form of electrical impulses. Full medical glossary
The system that gathers and stores information and is in overall control of the body. The brain and spinal cord form the central nervous system. Full medical glossary
Nerve cell. Full medical glossary
Affecting the whole body. Full medical glossary
A diagnostic method in which very high frequency sound waves are passed into the body and the reflective echoes analysed to build a picture of the internal organs – or of the foetus in the uterus. Full medical glossary
The means of producing immunity by stimulating the formation of antibodies. Full medical glossary